Peptide yy pharmaceutical formulations, compositions, and methods

ABSTRACT

Pharmaceutical compositions comprising PYY (e.g., PYY(3-36) and analogs and variants thereof), satiety peptides, satiety hormones, metabolic hormones, and methods of treating metabolic diseases with such compositions are provided. Aspects include methods of increasing a feeling of fullness in patients treated with pharmaceutical compositions comprising PYY, PYY(3-36), satiety peptides, satiety hormones, metabolic hormones, and analogs, receptor antagonists and variants thereof.

All references cited herein, including but not limited to patents andpatent applications, are incorporated by reference in their entirety.

BACKGROUND

The prevalence of obesity continues to increase worldwide [1]. In theUnited States, 69% of adults are overweight or obese [2]. However, thereis still a lack of effective, long-term, noninvasive treatments forobesity. The current “one treatment fits all” approach to obesity isassociated with highly variable efficacy and outcomes [3].

PYY(3-36) is a Y receptor (e.g., Y2 receptor) agonist released fromintestinal cells in response to feeding. Peptide YY (PYY) (3-36) is asatiation gut hormone released postprandially, mainly by the gut.PYY(3-36) secretion is related to caloric intake, and it inducessatiation by acting on Y2 receptors in the arcuate nucleus of thehypothalamus. Recently, murine and human PYY(3-36) was found to bepresent in saliva, and its concentration in saliva is correlated to itsconcentration in plasma. PYY(3-36) and Y2 receptors are expressed in thetaste cells in the circumvallate papilla of the tongue [4]. In mice,acute augmentation therapy with salivary PYY(3-36) induces highersatiation shown by feeding behavioral studies, and by c-Fos activationin the arcuate nucleus of the hypothalamus. Acute increase of salivaryPYY(3-36) resulted in a decrease in one-hour food intake in a dosedependent manner. The chronic over-expression of salivary PYY(3-36)using a viral vector-mediated gene delivered (rAAV-PYY vs rAAV-GFPcontrol) into submandibular salivary glands produced a two-fold chronicincrease of PYY(3-36) in saliva for 22 weeks [4]. The results of thistreatment showed a decrease in weekly food intake, and a 23% body weightloss 8 weeks after vector delivery compared to a control. PYY(3-36)induces satiation through saliva and taste cell receptors [5,6].

Incretins, such as glucagon-like peptide 1 (GLP-1), enhance glycemiccontrol, impede gastric emptying, and increase satiation in healthy andin diabetic patients [7-9]. GLP-1 and GLP-1 agonists reduce fasting andpostprandial glucose levels via increased insulin secretion from thepancreas, and reduced gluconeogenesis in the liver.

Exenatide (Exendin-4) is a 39-amino acid peptide produced in thesalivary gland of the Gila monster lizard. Its amino acid sequenceshares 53% identity with GLP-1, but its half-life is prolonged due toits resistance to rapid breakdown by dipeptidyl peptidase 4 (DPP-IV),the normal mechanism for GLP-1 inactivation. Exenatide, in both dailyand weekly formulations, has been approved by the FDA for treatment ofpatients with type 2 diabetes mellitus, where treatment with metforminor sulfonylureas inadequately controls the patient's condition. GLP-1receptor agonists also retard gastric emptying and decrease food intakeby 19% [10-12]. The effects of exenatide on gastric emptying aretemporally associated with reduced postprandial glycemia in patientswith type 2 diabetes mellitus [13].

Previously, PYY and PYY analogs were administered to patients in amanner resulting in a substantial increase in PYY levels in the plasmaof the subject. PYY and PYY analogs have also been used to inducesatiation in a subject without substantially changing the concentrationof PYY in the plasma of the subject. See, e.g., U.S. Pat. No. 9,492,505.Higher doses of PYY may result in undesirable side effects such asnausea. However, suitable low-dose PYY pharmaceutical formulations forinducing a feeling of fullness in a subject have not been described.

SUMMARY

It has been shown that local oral delivery of PYY(3-36) reduces foodintake and increases satiety. However, it is desirable to improve theactivity of PYY(3-36), PYY analogs, and satiety peptides by providing asuitable low-dose formulation to induce a long lasting feeling offullness in a subject. In addition, such formulations can be used fortreatment of metabolic disorders.

Aspects described herein provide pharmaceutical compositions comprisingPYY or PYY analogs (e.g., PYY(3-36)), variants, and satiety peptides(e.g., GLP-1, oxyntomodulin, and cholecystokinin) wherein the dose ofPYY or PYY analogs, variants, and satiety peptides in the pharmaceuticalcomposition is at least about 2.5 ng. In another aspect, PYY isPYY(3-36). In yet another aspect, the dose of PYY in the pharmaceuticalcomposition is from about 2.5 ng to about 2.5 mg. In another aspect, thedose of PYY in the pharmaceutical formulation is from about 2.5 μg toabout 250 μg. The term “dose” refers to an amount in the range of 90 to110% of the desired amount of an active pharmaceutical ingredient in adosage form or the claimed amount on a label for a Federal DrugAdministration (FDA) approved drug product.

In another aspect, the dose per volume of PYY(3-36) can range, forexample, from about 2.5 ng to about 250 μg in a volume from about 25 μlto about 100 μl or up to about 5 mls. In another aspect, the dose/volumeis about 2.5 μg/ml. In another aspect, the dose/volume is about 500μg/500 μL. In another aspect, the dose/volume is about 250 μg/ml.

In these aspects, the pharmaceutical compositions can further comprisepharmaceutically acceptable excipients (e.g., propylene glycol,potassium sorbate, l-arginine, edetate disodium, monosodium phosphate,and polysorbate 20). Optionally, the pharmaceutical formulations furthercomprise water or any other suitable diluent or pharmaceuticallyacceptable excipient. In one aspect, the pharmaceutical compositioncomprises excipients that further stabilize PYY(3-36) at a low dose pervolume (e.g., less than 2.5 ng/ml). In other aspects, the excipientsincrease residence time of the pharmaceutical compositions on thetongue, for example, promoting binding of PYY(3-36) to its receptor(e.g., Y2 receptor). In yet another aspect, excipients can be used toincrease retention time of PYY(3-36) in the saliva, to the extent suchan increase is desirable.

In another aspect, the pH of the pharmaceutical compositions ismaintained at a pH which promotes the activity and stability ofPYY(3-36). In one aspect, the pH of the pharmaceutical composition isbetween about pH 5 to about 8. In another aspect, the pH of thepharmaceutical composition is between about pH 6 to about 7. In yetanother aspect, the pH is about 5.

In one aspect, the described pharmaceutical formulations can be used totreat metabolic disorders (e.g., obesity, elevated blood sugar,diabetes, fatty liver disease, PCOS, and multiple sclerosis) byadministering PYY and PYY analog formulations to a subject, and reducingsymptoms associated with the metabolic disorders compared to a subjectthat has not received PYY or PYY analog formulations.

Yet another aspect provides methods of increasing a feeling of fullnessin a subject by administering a PYY or a PYY analog formulation to thesubject, for example, before a meal. In this aspect, the feeling offullness can last at least about 30, 60, 90, or 120 minutes or longerafter the PYY or PYY analog formulation is administered to subject andafter the subject has eaten a meal. In another aspect, thepharmaceutical composition is administered to the subject, and thesubject subsequently consumes a meal.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the results of an exemplary study where PYY(3-36) wasadministered intraorally to subjects at the indicated dose (GT-001 Doseon the x-axis), and a feeling of fullness (mean value on y-axis) wasassessed 30 minutes and 120 minutes after the subjects ate lunch;

FIG. 2 shows the results of an exemplary study where the feeling offullness (VAS Fullness (mm)) was plotted against the time post-treatmentwith PYY(3-36) (30 min, 60 min, 90 min, and 120 min) with a PYY(3-36)formulation, and after the subjects ate lunch at four doses (placebo, 25ng, 25 μg, and 250 μg); and

FIG. 3 shows the normalized concentration in pg/ml of PYY in the plasmaof subjects receiving placebo, 0.25 mg/ml PYY(3-36), and 2.5 mg/mlPYY(3-36) formulations (each followed by lunch) measured in a time rangeof up to 4 hours after administration.

DETAILED DESCRIPTION

Before describing an exemplary aspect described herein, it is to beunderstood that the invention is not limited to the details ofconstruction or process steps set forth in the following description.The aspects described herein are capable of being practiced or beingcarried out in various ways.

Satiation occurs during a meal. It's that point at which a subject feelsthat she has had enough to eat, and does not desire any more food.Satiety, on the other hand, describes a subject's experience after amealhow long before the subject starts to feel hungry again. A “feelingof fullness” refers to an indicator of satiety as reported by a personfollowing the eating of food or a meal. The degree and duration of afeeling of fullness (satiation and satiety) are predictor of whether aperson will continue to eat or resume eating and therefore increasecaloric intake over time. Thus, increasing the degree and duration of afeeling of fullness reduces overall caloric intake and a reduction inweight and obesity.

A Visual Analogue Scale (VAS) is an instrument, tool, or methodologyused to measure a characteristic that can vary in value or degree, andis otherwise not easily subject to direct measurement. For example, aVAS is often used to determine the degree of pain suffered by a patient(e.g., a scale of 1 to 10). Likewise, a VAS can be used reliably tomeasure the degree of fullness reported by a subject following theeating of food or a meal. See, e.g., Blundell et al., “Appetite Control:Methodological Aspects of The Valuation of Foods,” Obes Rev. 2010 March;11(3): 251-270; Flint et al., “Reproducibility, power and validity ofvisual analogue scales in assessment of appetite sensations in singletest meal studies,” International Journal of Obesity (2000) 24, 38-48(2000).

Metabolic disorders, diseases, or metabolic syndrome refers to diseasesor conditions that increase risk for diseases or disorders associatedwith, related to, or caused by abnormal metabolism (e.g., diabetes,heart disease, stroke, obesity, elevated blood sugar, fatty liverdisease, PCOS (polycystic ovary syndrome), and multiple sclerosis). Thelack of effective long term, non-invasive procedures for metabolicdisorders has spurred the search for small molecules capable of treatingthese conditions with minimal side effects. While several small moleculetherapeutics are currently on the market, their efficacy is relativelylow, and safety profiles are less than ideal. On the other hand, naturalhuman hormones responsible for regulation of hunger, satiety and energymetabolism in normal physiology, and their analogs, as described herein,can be used to treat such diseases.

GLP-1 receptor agonists, and PYY(3-36) and analogs have been used withlimited success in treating metabolic disorders. Therapeutic outcomeswith GLP-1 receptor agonists for diabetes mellitus (DM) and obesity arehighly variable, and result in significant side effects. While PYY(3-36)is a strong inducer of satiety, systemically administered PYY andanalogs tend to be associated with severe side effects, such as nauseaand vomiting.

Aspects described herein provide compositions comprising PYY and PYYanalogs such as PYY(3-36). In certain aspects, these compositions can beused to treat metabolic diseases (e.g., obesity, diabetes, elevatedblood sugar, etc.). These compositions can be used to reduce,ameliorate, or treat conditions in patients more effectively than simpleaqueous solutions or simple dry compositions.

In one aspect, the term “PYY(3-36)” or “native PYY-3-36” refers to aminoacids 3-36 of the human PYY molecules, having the following amino acidsequence (from amino to carboxy terminus):

{NH2}-ILE-LYS-PRO-GLU-ALA-PRO-GLY-GLU-ASP-ALA-SER-PRO-GLU-GLU-LEU-ASN-ARG-TYR-TYR-ALA-SER-LEU-ARG-HIS-TYR-LEU-ASN-LEU-VAL-THR-ARG-GLN-ARG-TYR- {COOH}.

Native PYY(3-36) is post-translationally processed from a precursorpeptide encoded by the following mRNA nucleic acid sequence (positions632-733 (bolded below)) encode the mature peptide):

1 gcccctggag gaactgaacc cactatcggt catggggccg agactaaatg tggcgggttg  61tctttaatct gctgccaaga ggaaactcat tcaggcaagt tcagcccttt atgaggaatt  121cccctgtggt cacattccaa ttcctggacc tgctgccacc ctcagaactg catgctcctt  181cttcagactt tctaagaatg actcaggtca ttggtggagt gaagtcaaga tttccaactc  241agtcacctga agagatggag ataccattca tggagctgga ggtccctgga gatttgggaa  301ttcagataac aagctaagat aaggagtttg cctacctctg tcctagagcg aagcctgagc  361cttgggcgcg cagcacacca caagtatctg ttactgtgtt ttgcagaagc ttcaggcggg  421gatataagcc ccacaaggaa agcgctgagc agaggaggcc tcagcttgac ctgcggcagt  481gcagcccttg ggacttccct cgccttccac ctcctgctcg tctgcttcac aagctatcgc  541tatggtgttc gtgcgcaggc cgtggcccgc cttgaccaca gtgcttctgg ccctgctcgt  601ctgcctaggg gcgctggtcg acgcctaccc catcaaaccc gaggctcccg gcgaagacgc  661ctcgccggag gagctgaacc gctactacgc ctccctgcgc cactacctca acctggtcac  721ccggcagcgg tatgggaaaa gagacggccc ggacacgctt ctttccaaaa cgttcttccc  781cgacggcgag gaccgccccg tcaggtcgcg gtcggagggc ccagacctgt ggtgaggacc  841cctgaggcct cctgggagat ctgccaacca cgcccacgtc atttgcatac gcactcccga  901ccccagaaac ccggattctg cctcccgacg gcggcgtctg ggcagggttc gggtgcggcc  961ctccgcccgc gtctcggtgc ccccgccccc tgggctggag ggctgtgtgt ggtccttccc  1021tggtcccaaa ataaagagca aattccacag aaacggaaaa aaaaaaaaa 

In another aspect, the term “PYY(3-36)” further comprises analogs orvariants of native PYY(3-36) that retain at least about 20, 30, 40, 50,60, 70, 80, 90 or 100% of the biological activity of native PYY(3-36).In this aspect, term “variants” refers to modifications to orsubstitutions of one or more amino acids of native PYY(3-36).Substitution of an amino acid refers to replacement of one amino acidwith another amino acid. In one aspect, an amino acid may be replacedwith an amino with a similar side group (e.g., acidic, basic, neutral).The term “biological activity” refers to the activation of Y receptorsby one or more small molecules described herein, producing an effect,either locally or systemically, on food intake, gastrointestinalfunction or central nervous system activity.

Analogs or variants of PYY(3-36) include, for example, the analogs orvariants of PYY. See, e.g., Michel et al., Dipeptidyl peptidase IVinhibitors in diabetes; more than inhibition of glucagon-like peptide-1metabolism? Naunyn-Schmiedeberg's Arch Pharmacol (2008) 377:205-207;Niida et al., Antiobesity and emetic effects of a short-length peptideYY analog and its PEGylated and alkylated derivatives, Bioorganic &Medicinal Chemistry (2017) (S0968-0896 (Epub ahead of print). In oneaspect, these analogs and variants can be used in the pharmaceuticalcompositions described herein.

Aspects described herein provide pharmaceutical compositions comprisingPYY, wherein the dose of PYY provided to a subject is at least about 2.5ng when the PYY is administered to the subject. In another aspect, PYYis PYY(3-36). In yet another aspect, the dose of PYY, PYY(3-36), orother PYY analogs is about 25 ng, 250 ng, 2.5 μg, 25 μg, 250 μg, or 2.5mg. In further aspects, the dose of PYY, PYY(3-36), or other PYY analogscan range from about 25 ng to about 2.5 mg, from about 250 ng to about250 μg, or from about 2.5 μg to about 25 μg.

Further aspects provide a pharmaceutical composition, comprising asatiety peptide in a dose of about 2.5 ng to about 2.5 mg, and apharmaceutically acceptable excipient. In another aspect, thepharmaceutical composition of claim 23, wherein the satiety peptide isselected from the group consisting of GLP-1, oxyntomodulin, andcholecystokinin.

In another aspect, the dose per volume of PYY(3-36) can range, forexample, from about 2.5 ng to about 250 μg in a volume from about 25 μlto about 5 mls of solvent (e.g., water, buffer, etc.). In anotheraspect, the dose/volume is about 2.5 μg/ml. In another aspect, thedose/volume is about 500 μg/500 μl. The volume of a pharmaceuticalformulation selected for delivering a dose of PYY(3-36) can be selected,for example, to optimize the residency time of PYY(3-36) in the oralcavity and, more specifically, the tongue in order to increase theinteraction between PYY(3-36) and its receptor on the tongue (e.g., Y2receptor).

Further aspects comprise these pharmaceutical compositions comprisingnucleotides encoding or peptides having substantial identity to PYY,PYY(3-36), or other PYY analogs in addition to one or more of thefollowing, or with one or more of the following in place of PYY,PYY(3-36), or other PYY analogs: GLP-1, oxyntomodulin, andcholecystokinin acetyl-CoA carboxylase-(ACC) inhibitor, a diacylglycerolO-acyltransferase 1 (DGAT-1) inhibitor, monoacylglycerolO-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, anAMPK activator, a sulfonylurea, a meglitinide, an α-amylase inhibitor,an α-glucoside hydrolase inhibitor, an α-glucosidase inhibitor, a PPARγagonist, a PPAR α/γ agonist, a biguanide, a glucagon-like peptide 1(GLP-1) modulator, GLP-1 receptor agonists, liraglutide, albiglutide,exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, aprotein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, adipeptidyl peptidease IV (DPP-IV) inhibitor, an insulin secreatagogue, afatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminalkinase (JNK) inhibitor, glucokinase activators (GKa), insulin, aninsulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2 receptoragonist, SGLT2 inhibitors, a glucagon receptor modulator, GPR119modulators, FGF21 derivatives or analogs, TGR5 receptor modulators,GPBAR1 receptor modulators, GPR40 agonists, GPR120 modulators, highaffinity nicotinic acid receptor (HM74A) activators, SGLT1 inhibitors,inhibitors or modulators of carnitine palmitoyl transferase enzymes,inhibitors of fructose 1,6-diphosphatase, inhibitors of aldosereductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2,inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCα,PKCβ, PKCγ), inhibitors of fatty acid synthetase, inhibitors of serinepalmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105,Kv1.3, retinol binding protein 4, glucocorticoid receptor, somato stainreceptors, inhibitors or modulators of PDHK2 or PDHK4, inhibitors ofMAP4K4, modulators of IL1 family including IL1beta, HMG-CoA reductaseinhibitors, squalene synthetase inhibitors, fibrates, bile acidsequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors,cholesterol absorption inhibitors, PCSK9 modulators, cholesteryl estertransfer protein inhibitors and modulators of RXRα, GIP receptoragonists, enterostating and enterostatin analogs, amylin and amylinreceptor agonists, ghrelin modulators (e.g., inhibitors) and leptin andleptin receptor agonists, pancreatic polypeptide (PP), calcitonin, OXM,neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovinegrowth hormone, porcine growth hormone, ghrelin, ghrelin receptorantagonists, and glucagon and analogs and variants thereof.

In yet another aspect, pharmaceutical compositions comprising one ormore active pharmaceutical ingredients selected from the groupconsisting of PYY, PYY(3-36), GLP-1, oxyntomodulin, and cholecystokinin,acetyl-CoA carboxylase-(ACC) inhibitor, a diacylglycerolO-acyltransferase 1 (DGAT-1) inhibitor, monoacylglycerolO-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, anAMPK activator, a sulfonylurea, a meglitinide, an α-amylase inhibitor,an α-glucoside hydrolase inhibitor, an α-glucosidase inhibitor, a PPARγagonist, a PPAR α/γ agonist, a biguanide, a glucagon-like peptide 1(GLP-1) modulator, GLP-1 receptor agonists, liraglutide, albiglutide,exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, aprotein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, adipeptidyl peptidase IV (DPP-IV) inhibitor, an insulin secreatagogue, afatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminalkinase (JNK) inhibitor, glucokinase activators (GKa), insulin, aninsulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2 receptoragonist, SGLT2 inhibitors, a glucagon receptor modulator, GPR119modulators, FGF21 derivatives or analogs, TGR5 receptor modulators,GPBAR1 receptor modulators, GPR40 agonists, GPR120 modulators, highaffinity nicotinic acid receptor (HM74A) activators, SGLT1 inhibitors,inhibitors or modulators of carnitine palmitoyl transferase enzymes,inhibitors of fructose 1,6-diphosphatase, inhibitors of aldosereductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2,inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCα,PKCβ, PKCγ), inhibitors of fatty acid synthetase, inhibitors of serinepalmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105,Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostainreceptors, inhibitors or modulators of PDHK2 or PDHK4, inhibitors ofMAP4K4, modulators of IL1 family including IL1beta, HMG-CoA reductaseinhibitors, squalene synthetase inhibitors, fibrates, bile acidsequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors,cholesterol absorption inhibitors, PCSK9 modulators, cholesteryl estertransfer protein inhibitors and modulators of RXRα, GIP receptoragonists, enterostating and enterostatin analogs, amylin and amylinreceptor agonists, ghrelin modulators (e.g., inhibitors) and leptin andleptin receptor agonists, pancreatic polypeptide (PP), calcitonin, OXM,neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovinegrowth hormone, porcine growth hormone, ghrelin, ghrelin receptorantagonists, and glucagon and a pharmaceutically acceptable excipient.In this aspect, these active ingredients can be formulated attherapeutic doses, and if the second drug is PYY or PYY(3-36), its dosecan be at from about 2.5 ng to about 2.5 mg. The term “therapeutic dose”refers to a dose at which a pharmaceutically active ingredient cantreat, ameliorate, or reduce symptoms associated with a disease,disorder, or condition.

In another aspect, these pharmaceutical compositions further comprisepharmaceutically acceptable excipients (e.g., propylene glycol,potassium sorbate, l-arginine, edetate disodium, monosodium phosphate,and polysorbate 20). In one aspect, propylene glycol is present in aconcentration of about 100 mg/ml, 1-arginine is present in aconcentration of about 25 mg/ml, potassium sorbate is present in aconcentration of about 2 mg/ml, edetate disodium is present in aconcentration of about 1.2 mg/ml, sodium phosphate monobasic dihydrateis present in a concentration of about 7.8 mg/ml, and polysorbate ispresent in a concentration of about 5 mg/ml. Further aspects comprisethese pharmaceutical compositions with GLP-1, oxyntomodulin, andcholecystokinin in place of PYY, PYY(3-36), or other PYY analogs andvariants.

For example, the pharmaceutical compositions described herein caninclude co-solvent stabilizers like propylene glycol or other suitableco-solvent stabilizers (e.g., lower molecular weight polyethyleneglycols (PEG) such as PEG 200 and 400, glycerin, and ethanol (alcohol)).

In another aspect, the pharmaceutical compositions described herein caninclude amino acid stabilizers like L-Arginine or other suitable aminoacid stabilizers (e.g., alanine, arginine, aspartic acid, glycine,lysine, proline, and methionine).

In yet another aspect, the pharmaceutical compositions described hereincan include preservatives like potassium sorbate, or other suitablepreservatives (e.g., ascorbic acid, benzyl alcohol, benzoic acid, citricacid, chlorobutanol, m-cresol, glutathione, methionine, methylparaben,propylparaben, sodium sulfite, parahydroxybenzoate esters(methylhydroxybenzoate and propylhydroxybenzoate), boric acid and boratesalts, sorbic acid and other sorbate salts besides potassium, andphenolics)).

In another aspect, the pharmaceutical compositions described herein caninclude antioxidants such as edetate disodium or another suitableantioxidant (e.g., sodium formaldehyde sulphoxylate, butylatedhydroxyanisole, and butylated hydroxytoluene). In another example, thepharmaceutical compositions described herein can include buffers likephosphate or other suitable buffers (e.g., acetate, carbonate, citrate,citrate-phosphate, glycine, HEPES, histidine, maleate, phosphate,succinate, tartrate, and triethanolamine (Tris)). In another example,the pharmaceutical compositions described herein can include surfactantslike polysorbate 20 or other suitable surfactants (e.g., Poloxamer188/407, polysorbate 40 or 80, or sodium lauryl sulfate).

In yet another aspect, the excipients include flavorings to increasecompliance with ingesting the pharmaceutical formulation. For example,the flavorings can be used to mask bitter or other undesirable flavorproperties, or to make the pharmaceutical formulation compatible withthe flavor of food that may be ingested before or after thepharmaceutical formulations. Compatible flavorings include, for example,apple, banana, bubblegum, cherry, chocolate, grape, lemon, mango,orange, raspberry, strawberry, vanilla, watermelon, mint or acombination of the above flavors. In another aspect, these flavoringsare dye-free, sugar-free, hypoallergenic, gluten-free, and casein-free.

In one aspect, the pharmaceuticals compositions described herein areadapted for delivery to the oral cavity (e.g., intraoral, oromucosal,transmucosal, topical lingual, gargles, mouthwashes, gingival solutions,oromucosal solutions and oromucosal suspensions, semi-solid oromucosalpreparations (including for example gingival gel, gingival paste,oromucosal gel, oromucosal paste)), oromucosal drops, oromucosal spraysand sublingual sprays (including oropharyngeal sprays), dry powdersprays, lozenges and pastilles, compressed lozenges, sublingual tabletsand buccal tablets, oromucosal capsules, mucoadhesive preparations)).See, e.g., Oromucosal Preparations, (Ph Eur monograph 1807). In anotheraspect, the PYY in the pharmaceutical composition is adapted for bindingto the Y2 receptor.

The term “adapted for delivery” refers to a pharmaceutical formulationor ingredient that has properties or is configured to be preferentiallydelivered or bound to a desired area of the body (e.g., mouth, tongue)or a target (e.g., a receptor). The term “adapted for delivery to theoral cavity” refers to a pharmaceutical formulation that canpreferentially deliver PYY(3-36) to the oral cavity or, morespecifically, the tongue or one or more active substances intended foradministration to the oral cavity and/or the throat to obtain a local orsystemic effect. See, e.g., Oromucosal Preparations, (Ph Eur monograph1807). The term “adapted for binding to a receptor” or “adapted forbinding to the Y2 receptor,” refers to a satiety peptide, analog, orother active ingredient that has a binding affinity to the Y2 receptoror residence time on the tongue sufficient to induce satiety (e.g.,about 30 seconds to about 1 min). In one aspect, “local oral delivery”can refer to obtaining a local effect without increasing the levels ofan active ingredient in the blood plasma.

The excipients in such a pharmaceutical formulation are compatible withthe mouth for intraoral delivery, and the active ingredient in thepharmaceutical formulation can maintain its activity in the mouth untildelivered to its site of activity. In another aspect, PYY(3-36) isdelivered to the tongue, and binds to a Y receptor (e.g., the Y2receptor).

In this aspect, PYY(3-36) can bind to the tongue, and transmit a signalto the brain via a receptor (e.g., Y2 receptor). In another aspect,PYY(3-36) can be delivered systemically by any suitable route ofadministration (e.g., oral, parenteral, intravenous, etc.).

The term “binds” refers to an association between PYY(3-36) (or othersatiety peptides and metabolic hormones as described herein) or aportion of the PYY(3-36) molecule, and a Y receptor through a chemicalbond (e.g., ionic, covalent, or hydrophobic) or other chemical orphysical attraction between PYY(3-36) or a portion thereof and a Yreceptor where a biological response is induced by the associationbetween PYY(3-36) and the Y receptor. See e.g., Doods, Receptor bindingprofiles of NPY analogues and fragments in different tissues and celllines, Peptides. 1995; 16(8):1389-94.

In another aspect, the pharmaceutical compositions comprise excipientsthat increase the time PYY(3-36) is in contact with the mucosa (e.g.,viscosity enhancement, encapsulation, and controlled release). Withoutbeing bound by theory, it is believed that increasing the contact timeof the pharmaceutical formulation with the mucosa, leads to increasedbinding of PYY(3-36) to its receptor on the tongue. Suitable excipientsfor viscosity enhancement include rheology modifiers which also may bemucoadhesive such as methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, alginic acid, polyvinylpyrrolidone, and sodiumcarboxymethylcellulose. Suitable excipients for modified release of thePYY(3-36) in the oral cavity include mucoadhesive permeation enhancerssuch as 23-lauryl ether, aprotinin, azone, benzalkonium chloride,cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrins,dextran sulfate, and lauric acid. Other suitable mucoadhesive polymersused for buccal or intraoral delivery include agarose, chitosan,gelatin, hyaluronic acid, gums (e.g. guar, hakea, xanthan, gellan,carrageenan, pectin, and sodium alginate), cellulose derivatives (e.g.,CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC,methylhydroxylethylcellulose), poly (acrylic acid)-based polymers (e.g.,CP, PC, PAA, polyacrylates, poly(methylvinylether-co-methacrylic acid),poly(2-hydroxyethyl methacryalate), poly(alkylcyanoacryalate),poly(isohexylcyanocrylate), poly(isobutylcyanoacrylate), copolymer ofacrylic acid and PEG, poly(N-2-hydroxypropyl methacrylamide), PHPMAm,polyoxyethylene, PVA, PVP, and other thiolated polymers; scleroglucan,PVA, steroidal detergents, non-ionic surfactants, laureth-9, sodiumfusidate, included sodium lauryl, sodium laurate (e.g., pH 8.9),palmitoyl carnitine, lauric acid/propylene glycol vehicle, Brij 78,sodium deoxycholate, sodium lauryl sulfate, lecithin and PVP. See, e.g.,International Journal of Pharmaceutics, Volume 53, Issue 3, 1 Aug. 1989,Pages 227-235.

In another aspect, the pharmaceutical compositions comprise excipientsthat increase the residence time of PYY(3-36) in the saliva (e.g., theamount of time PYY(3-36) remains in the saliva without significantdegradation of the peptide). Without being bound by theory, it isbelieved that increasing the residence time of PYY(3-36) in the salivaincreases the opportunity for PYY(3-36) to bind its receptor on thetongue. The residence time in the saliva can optionally be adjusted toavoid increasing systemic exposure to PYY(3-36) through, for example,swallowing.

The term “pharmaceutically acceptable excipients” includes, for example:

(1) Stabilizers (e.g., co-solvents like propylene glycol, polyethyleneglycols (PEG), glycerin, and ethanol (alcohol)) and amino acids (e.g.,alanine, L-Arginine, arginine, aspartic acid, glycine, lysine, proline,and methionine).

(2) Preservatives (e.g., potassium sorbate, ascorbic acid, benzylalcohol, benzoic acid, citric acid, chlorobutanol, m-cresol,glutathione, methionine, methylparaben, propylparaben, sodium sulfite,parahydroxybenzoate esters (methylhydroxybenzoate andpropylhydroxybenzoate), boric acid and borate salts, sorbic acid andsorbate salts, and phenolics).

(3) Antioxidants (e.g., edetate disodium, sodium formaldehydesulphoxylate, butylated hydroxyanisole, and butylated hydroxytoluene);

(4) Buffers (e.g., phosphate, acetate, carbonate, citrate,citrate-phosphate, glycine, HEPES, histidine, maleate, phosphate,succinate, tartrate, and triethanolamine (Tris));

(5) Surfactants (e.g., polysorbate 20, poloxamer 188/407, polysorbate20/40/80, and sodium lauryl sulfate);

(6) Rheology modifiers (e.g., methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, alginic acid, polyvinylpyrrolidone, and sodiumcarboxymethylcellulose);

(7) Mucosal Permeation Enhancers (e.g., 23-lauryl ether, aprotinin,azone, benzalkonium chloride, cetylpyridinium chloride,cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, andlauric acid);

(8) Excipients used to stabilize active ingredients in lyophilizedtablets for oral disintegration and dissolution in the oral cavityincluding sugars or sugar alcohols such as sucrose, trehalose, mannitol,dextrose, and polyvinylpyrrolidone (PVP) or glycine;

(9) Flavorings like apple, banana, bubblegum, cherry, chocolate, grape,lemon, mango, orange, orange swirl, raspberry, strawberry, strawberryswirl, vanilla, walberry swirl, and watermelon (including dye-free,sugar-free, hypoallergenic, gluten-free, and casein-free versions); andsweetening agents, including sucrose, liquid glucose, glycerol,sorbitol, saccharin sodium and aspartame); and

In one aspect, delivery of PYY(3-36) compositions to the tongueminimizes or eliminates any substantial systemic delivery of PYY(3-36).The term “substantial systemic delivery” refers to blood levels ofadministered PYY(3-36) or its analogs or variants that exceed the limitof detection, are distinguishable from circulating levels, or cause asignificant increase in circulating levels.

Further aspects provide methods of treating metabolic disorders ordiseases in a subject. In another aspect, the metabolic disease can beselected from the group consisting of obesity, elevated blood sugar(e.g., elevated blood sugar levels), diabetes, fatty liver disease, highblood pressure, PCOS, and multiple sclerosis. In these aspects,“treatment” or “treat” refers to administering PYY (e.g., PYY(3-36)) oranother PYY analog) to a patient having the indicated metabolic disease.

When the metabolic disorder is obesity, food intake by the subject isreduced by at least about 20% in the subject after treatment with a doseof the pharmaceutical composition compared to a subject who did notreceive treatment. In another aspect, body weight of the subject isreduced by at least about 5% after treatment with a dose of thepharmaceutical composition compared to a subject who did not receivetreatment. In the aspects described herein, the term “subject” refers toan animal (e.g., human, non-human) in need of treatment for theindicated disease or condition.

When the metabolic disorder is elevated blood sugar (e.g.,pre-diabetes), the blood sugar or glucose levels of a subject is reducedby at least about 10% after treatment with a dose of the pharmaceuticalcomposition compared to a subject who did not receive treatment. Inanother aspect, the fasting glucose level is reduced by at least about10% after treatment with a dose of the pharmaceutical compositioncompared to a subject who did not receive treatment.

When the metabolic disease is disorder, the area under the curve (AUC)in a glucose tolerance test of a subject is reduced by at least about15% after treatment with a dose of the pharmaceutical compositioncompared to a subject who did not receive treatment. In another aspect,HbA1c levels in a subject are reduced by at least about 15% aftertreatment with a dose of the pharmaceutical composition compared to asubject who did not receive treatment.

When the metabolic disorder is fatty liver disease, the liver fatconcentration in a subject is reduced by about 20% after treatment witha dose of the pharmaceutical composition compared to a subject who didnot receive treatment. In this aspect, liver fat concentration can bemeasured by, for example, liver biopsy, ultrasound, MRI (magneticresonance imaging), and elastography.

When the metabolic disorder is PCOS, PCOS symptoms in a subject arereduced by at least about 15 to 20% after a dose of the pharmaceuticalcomposition compared to a subject who did not receive the dose. In thisaspect, the exemplary symptoms include, but are not limited to, hormonalprofile (e.g., thyroid function tests, serum prolactin levels, and afree androgen index (defined as total testosterone divided by sexhormone binding globulin [SHBG]×100, to give a calculated freetestosterone level), LH2FsH ratio, and testosterone level).

When the metabolic disorder is multiple sclerosis (MS), multiplesclerosis symptoms are reduced in a subject by at least about 20% aftertreatment with a dose of the pharmaceutical composition compared to asubject who did not receive treatment. In this aspect, the symptomsinclude, but are not limited to, the Multiple Sclerosis FunctionalComposite. See, e.g., Cutter et al., Development of a multiple sclerosisfunctional composite as a clinical trial outcome measure, Brain, 1999May; 122 (Pt 5):871-82.

When the metabolic disorder is high blood pressure, systolic anddiastolic blood pressure levels in a subject are reduced by at leastabout 20% after treatment with a dose of the pharmaceutical compositioncompared to a subject who did not receive treatment. In this aspect, forexample, treatment can be started when systolic and diastolic bloodpressure levels of 140 mm Hg or greater or at diastolic levels of 90 mmare reached.

The term “metabolic disorder” refers to a human or animal condition ordisease resulting from abnormal function or control of the metabolicsystem (e.g., obesity, diabetes, fatty liver disease, PCOS, and elevatedblood glucose levels). The term “disorder” generally refers todisruption to regular bodily structure and function or apathophysiological response to internal or external factors.

Further aspects provide methods of increasing a feeling of fullness in asubject comprising administering the pharmaceutical compositionsdescribed herein to the subject. In this aspect, the dose of PYY,PYY(3-36) or a variant or analog can be about 25 ng, 250 ng, 2.5 μg, 25μg, 250 μg, or 2.5 mg. In further aspects, the dose of PYY, PYY(3-36) ora variant or analog can range from about 25 ng to about 2.5 mg, fromabout 250 ng to about 250 μg, or from about 2.5 μg to about 25 μg. Inyet another aspect, the feeling of fullness in the subject can last atleast 30, 60, 90, or 120 minutes after treatment and after eating ameal. In another aspect, the pharmaceutical composition is administeredto the subject, and the subject subsequently consumes a meal.

In this aspect, the dose per volume of PYY(3-36) can range, for example,from about 2.5 ng to about 250 μg in a volume from about 25 μl to about5 mls. In another aspect, the dose/volume is 2.5 μg/ml. In anotheraspect, 500 μg/500 μL. The volume of a pharmaceutical formulationselected for delivering a dose of PYY(3-36) can be selected, forexample, to optimize the residency time of PYY(3-36) in the oral cavityand, more specifically, the tongue in order to increase the interactionbetween PYY(3-36) and its receptor on the tongue (e.g., Y2 receptor).

The term “eating a meal” refers a subject eating food with a totalcaloric intake of at least about, for example, 300-2000, 500-1000calories, or 300-800 calories. The term “feeling of fullness” refers toa subject self-reporting satiety following eating a meal as measuredusing, for example, VAS measurement wherein the VAS measurement isincreased by at least about 10%. In another aspect, the VAS measure isincreased by at least about 20%. In another aspect, a functionalmagnetic resonance imaging (“fMRI”) scan before and after treatment canbe used to measure a feeling of fullness (by measuring blood flowchanges in specific regions of the brain, for example the satietycenters of the brain stem, such as the nuclues tractus solitaris, andthe hypothalamus, such as the lateral hypothalamic area). In yet anotheraspect, subjects can verbally report a level of feeling of fullnessbefore and after treatment. In yet another aspect, subjects can verballyreport a level of feeling of fullness before and after treatment.

In one aspect, the pharmaceutical compositions comprising PYY(3-36) canbe delivered to a subject in need of treatment before, after, or duringa meal. In this aspect, the pharmaceutical compositions can be deliveredintraorally.

In one aspect the composition can be incorporated in any suitable dosageform (e.g., a lozenge, a dissolvable material, a dissolvable planarsheet, chewing gum, or a solid or semi-solid candy). In another aspect,the composition can be incorporated in a liquid formulation (e.g.,emulsion, a syrup, an elixir, a suspension, or a solution). In a furtheraspect, the composition can be incorporated in a spray for oraladministration, or drops for oral administration.

In one aspect, the pharmaceutical composition is as follows:

TABLE 1 Exemplary PYY(3-36) Pharmaceutical Formulation Strength (labelclaim) Component and Quantity Quality per unit Standard Function (mg/mL)% PYY₃₋₃₆, human Drug substance 2.5 ng/mL to 2.5 × 10⁻⁷ to 0.25% 2.5mg/mL Propylene Glycol, Stabilizer 100 10 USP L-Arginine, FreeStabilizer 25 2.5 Base, USP Potassium Sorbate, Preservative 2 0.20 NFEdetate Disodium, Antioxidant 1.2 0.12 Dihydrate, USP Sodium Phosphate,Buffer 7.8 0.78 Monobasic, Dihydrate, USP Polysorbate 20, NF Surfactant5 0.50 Hydrochloric Acid pH modifier QS to pH (HCl), NF, USP 7.0 ± 0.1Sodium Hydroxide pH modifier QS to pH (NaOH), USP 7.0 ± 0.1 SterileWater for Solvent QS to QS to Injection, USP 1 mL 100%

An exemplary clinical trial was performed as a dose-escalation designtrial. Approximately twelve evaluable subjects (n-12) with BMIs of 30 to40 kg/m² received a single dose of placebo followed by study drug(PYY(3-36) also known as GT-001) applied directly to the surface of thelingual mucosa with a disposable pipette followed by a one-day washout.A total of seven (7) doses was escalated to a dose of 2.5 mg/ml.

Without being bound by theory, it is believed that food intake isregulated by two opposing mechanisms; appetite and satiation. Bothmechanisms are regulated by the brain-gut axis. A fasting period inducesappetite by secretion of ghrelin from the stomach. Ghrelin acts onspecialized neurons in the arcuate nucleus of the hypothalamus toactivate the agouti-related peptide/NPY (AgRP/NPY) pathway. The AgRP/NPYpathway is responsible for stimulating appetite centers in the cerebralcortex that prepare the gastrointestinal tract for food intake andstimulate food-seeking behavior. Food intake then stimulates secretionof satiation hormones in the gut including PYY(3-36), oxyntomodulin, andglucagon-like peptide-1 (GLP-1). These hormones stimulate thepro-opiomelanocortin/alpha-melanocyte stimulation hormone (POMC/αMSH)pathway. The POMC/αMSH pathway stimulates different receptors in thecerebral cortex to produce a sensation of satiation and food reward(Acosta et al., 2014).

It was recently demonstrated that PYY(3-36) is also present in bothmurine and human saliva. In mice, salivary PYY(3-36) derives from bothplasma and is also synthesized in the taste cells in taste buds of thetongue [2]. Moreover, the cognate receptor, Y2R, is expressed in thetongue epithelia (Acosta, et al. 2011; Hurtado et al., 2012). Inaddition, all other YRs (Y1R, Y4R, and Y5R) are abundantly expressed inmultiple lingual cell types, including epithelial progenitors,keratinocytes, neuronal dendrites and taste receptor cells (TRCs)(Hurtado et al., 2012). We showed that PYY expressed in TRCs modulatesresponsiveness to bitter-tasting stimuli and to lipids (La Sala, FASEB,2013).

Previous results demonstrated that augmentation of salivary PYY(3-36) orExendin-4 result in a decrease in 1-hour food intake (Acosta et al.,2011). The effect is peptide-specific; similar studies with neuropeptideY or amylin resulted in no effect on food intake. Moreover, it was shownthat there is a dose-response effect. At the lower dose, 0.3 μg/100 gPYY(3-36), treated mice reduced their caloric intake by 16% as comparedto controls. (PYY(3-36) 3.44±0.06 kcal vs. vehicle 4.10±0.04 kcal,p=0.01) At the intermediate dose, 3 μg/100 g PYY(3-36), the reductionwas 26%. (PYY(3-36) 3.01±0.06 kcal vs. vehicle 4.10±0.04 kcal, p=0.008).At the higher dose, 10 μg/100 g PYY(3-36), the caloric intake wasfurther reduced by 42%. (PYY(3-36) 2.36±0.05 kcal vs. vehicle 4.10±0.04kcal, p=1.81E-06) (Acosta et al., 2011). However, the doses of PYY usedin these studies are significantly higher than described in aspectsherein and could result in undesired side effects and lack of efficacy(e.g., tachiphylaxsis−loss of response at higher doses) in humans.

The effects of PYY are mediated through the activation of specific Y2receptors expressed on the lingual epithelial cells. In a long-termstudy involving diet-induced obese (DIO) mice, a sustained increase inPYY(3-36) was achieved using viral vector-mediated gene deliverytargeting salivary glands (Acosta et al., 2014). The chronic increase insalivary PYY(3-36) resulted in a significant long-term reduction in foodintake and body weight. Augmentation of salivary PYY(3-36), whilereliably inducing strong anorexic responses, does not cause tasteaversion, a surrogate of nausea in rodents (Hurtado et al., 2013).Salivary PYY(3-36) activated forebrain areas known to mediate feeding,hunger, and satiation while minimally affecting brainstem chemoreceptorzones that trigger nausea. By comparing neuronal pathways activated bysystemic versus salivary PYY(3-36), a metabolic circuit was identifiedassociated with Y2R-positive cells on the tongue and extending throughbrainstem nuclei into hypothalamic satiety centers.

In accordance with aspects disclosed herein, this alternative circuitregulates ingestive behavior (e.g., promotes a feeling of fullness overtime) without inducing taste aversion. Aspects described herein providePYY (e.g., PYY(3-36)) formulations for the treatment of obesity viadirect lingual application and without concomitant nausea.

TABLE 2 Dose Escalation Study Study Visit Day DOSE of PYY(3-36) DOSEPYY(3-36) in 1 ml Day 1 placebo placebo Day 2 2.5xE−6 mg 2.5xE−3 μg Day4 2.5xE−5 mg 2.5xE−2 μg Day 6 2.5xE−4 mg 2.5xE−1 μg Day 8 2.5xE−3 mg 2.5μg Day 10 2.5xE−2 mg 25 μg Day 12 2.5xE−1 mg 250 μg Day 14 2.5 mg 2.5 mg

Table 2 shows an exemplary dose-escalation study from Day 1 through Day14 with two day intervals between doses after Day 2. The dose can beprepared, for example, from a stock solution of 2.5 mg/ml PYY(3-36).

FIG. 1 shows the results of an exemplary study where PYY(3-36) in 12subjects. PYY(3-36) was administered to subjects at the indicated dose(GT-001 Dose on the x-axis), and a feeling of fullness (mean value ony-axis) was assessed by VAS 30 minutes and 120 minutes after lunch. Asshown in FIG. 1, the feeling of fullness is significantly above placebolevel at a dose of 25 ng at 120 minutes post-lunch (VAS score of 7),increases at a dose of 2.5 μg, and reaches about 8 on the VAS scale at adose of 250 μg.

FIG. 2 shows the results of an exemplary study where the feeling offullness (VAS Fullness (mm)) was plotted against the time post-treatment(30 min, 60 min, 90 min, and 120 min) with PYY(3-36) and after thesubject ate lunch at four doses (placebo, 25 ng, 25 μg, and 250 μg). Asshown in FIG. 2, doses at 25 μg and 250 μg maintain a VAS score of 8 outto 120 minutes post-lunch. A dose of 25 ng results in a VAS score ofabout 8 up to 60 minutes post-lunch.

FIG. 3 shows the normalized concentration in pg/ml of PYY in the plasmaof subjects receiving placebo, 0.25 mg/ml PYY(3-36), and 2.5 mg/mlPYY(3-36) (each followed by lunch) measured in a time range of up to 4hours after administration. As shown, administering the placebo followedby food consumption induces the known and expected endogenous productionof PYY resulting from food consumption peaking at approximately 20 μg/mlabove pre-dose levels at 1-2 hours post-administration. Administeringexogenous PYY(3-36) to subjects does not raise the level of PYY inplasma above levels induced by the placebo/meal combination.

Further aspects provide additional exemplary PYY(3-36) dosage forms andformulations, including, but not limited to, the following:

TABLE 3 Oral Film Strip Strength (label claim) Component and QuantityQuality per unit Standard Function (mg) % PYY₃₋₃₆, human Drug substance2.5 ng to 5 × 10⁻⁷ to 0.5 2.5 mg Carboxmethylcellulose Polymer 225 45Polyethylene glycol Plasticizer 100 20 Eugradit RL-100 Polymer 94.5 18.9Polysorbate 20 Surfactant 25 5 Aspartame Sweetening 15 3 agent Citricacid Saliva 15 3 stimulating agent, preservative FD&C Blue No. 2 Color0.5 0.1 Aluminum Lake Peppermint Flavor 10 2 Ethanol Solvent — —Purified Water Solvent — — Total 500 100

Solvents are removed during manufacture.

Further aspects provide exemplary oral film strip dosage forms as shownin Table 3. In one aspect, oral film strip pharmaceutical compositionscomprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In thisaspect, the oral film strip pharmaceutical composition can compriseabout 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In another aspect,the oral film strip pharmaceutical composition further comprises asuitable polymer, plasticizer, sweetening agent, saliva stimulatingagent, preservative, and optional coloring, flavorings, and solvents.See e.g., Bala, et. al., Orally dissolving strips: A new approach tooral drug delivery system, Int J Pharm Investig. 2013 April-June; 3(2):67-76; Tomar, Formulation and Evaluation of Fast Dissolving Oral Film ofDicyclomine as potential route of Buccal Delivery, International Journalof Drug Development & Research April-June 2012 Vol. 4 Issue 2 ISSN0975-9344.

TABLE 4 Troche Strength (label claim) Component and Quantity Quality perunit Standard Function (mg) % PYY₃₋₃₆, human Drug substance 2.5 ng to2.0 × 10⁻⁷ to 0.2 2.5 mg Polyethylene glycol Vehicle or Base 963.8 79Acacia Suspending 183 15 agent Stevia Sweetener 36.6 3 Peppermint Flavor24.4 2 Total 1220 100

Further aspects provide exemplary troche dosage forms as shown in Table4. In one aspect, troche pharmaceutical compositions comprising about2.5 ng 2.5 mg of PYY(3-36) are provided. In this aspect, the trochepharmaceutical composition can comprise about 2.5 ng, 25 ng, 250 ng, and2.5 μg of PYY(3-36). In one aspect, the troche dosage form comprisesPYY(3-36), a vehicle or base, and a suspending agent.

In these aspects, the suspending agent, sweetener, and flavoringcomponents are optional. In another aspect, the vehicle or base of thetroche can be sugar, made adhesive by admixture with acacia ortragacanth, fruit paste (e.g., made from black or red currants),confection of rose, or balsam of tolu. See, e.g., Kamini et al.,Formulation and Percentage Evaluation of Gum-Acacia as A Binder W. S. R.to Jwaraghani Gutika (Herbo-Mineral Preparation, Int J Res Med. 2016;5(1); 21-24 (2016).

TABLE 5 Lollipop Strength (label claim) Component and Quantity Qualityper unit Standard Function (mg/mL) % PYY₃₋₃₆, human Drug substance 2.5ng to 1.25 × 10⁻⁷ to 0.125 2.5 mg EMDEX (hydrated Filler, 1640 82dextrose (dextrose Sweetener monohydrate) containing about 7%maltodetrin Disodium hydrogen Buffer  16 0.8 phosphate Citric acidPreservative  10 0.5 Raspberry Flavor   4 0.2 Confectionary sugarFiller,  310 15.5 Sweetener Magnesium stearate Lubricant  20 1 Total  2000 mg 100

Further aspects provide exemplary lollipop dosage forms as shown inTable 5. In one aspect, lollipop pharmaceutical compositions cancomprise about 2.5 ng 2.5 mg of PYY(3-36) are provided. In this aspect,the lollipop pharmaceutical composition comprises about 2.5 ng, 25 ng,250 ng, and 2.5 μg of PYY(3-36). In one aspect, the lollipop dosage formcomprises PYY(3-36), a filler, buffer, lubricant and a preservative.Flavoring, sweetener, are optional components. In another aspect, thelollipop dosage form further comprises maltose-dextrose, water, andcornstarch or another binding material. In another aspect, the lollipopdosage form further comprises maltose-dextrose, water, and cornstarch oranother binding material. See, e.g., US Patent Application Publication2007/0104763.

TABLE 6 Chewing Gum Strength (label claim) Component and QuantityQuality per unit Standard Function (mg/mL) % PYY₃₋₃₆, human Drugsubstance 2.5 ng to 2.5 × 10⁻⁷ to 0.25 2.5 mg Compressible Gum Gum base883 88.3 Base Powder (e.g., Health in Gum ®) Sorbitol Granulating 100 10agent, Sweetener Magnesium stearate Lubricant  10 1 Citric acidPreservative,  5 0.5 salivating agent Peppermint Flavor  2 0.2 Total 1000 mg 100

Further aspects provide exemplary chewing gum dosage forms as shown inTable 6. In one aspect, chewing gum pharmaceutical compositionscomprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In thisaspect, the chewing gum pharmaceutical composition can comprise about2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In one aspect, thechewing gum dosage form comprises PYY(3-36), a gum base, a granulatingagent, a lubricant, a preservative, and a lubricant. Flavoring, andsweeteners are optional components. See, e.g., Aslani, et al., Medicatedchewing gum, a novel drug delivery system, J. Res Med Sci. 2015 April;20(4): 403-411. Alternatively, chewing gum dosage forms can be made bydirect compression. See, e.g., U.S. Pat. No. 7,208,186. See, also, Heemaet. al., Medicated chewing gums-updated review. Int J Pharm Res Dev.2010; 2:66-76.

Further aspects provide spray-dried particle dosage forms (e.g., sachetof spray-dried particles) as shown in Tables 7-9. In these aspects,pharmaceutical compositions comprising about 2.5 ng 2.5 mg of PYY(3-36)are provided. The exemplary spray-dried pharmaceutical compositioncomprises about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36).

TABLE 7 Spray-Dried Particles, Example 1 Strength (label claim)Component and Quantity Quality per unit Standard Function (mg/mL) %PYY₃₋₃₆, human Drug substance 2.5 ng to 2.5 × 10⁻⁷ to 0.25 2.5 mgAnhydrous α Caarrier 800 80 Lactose Sorbitol Granulating  93 10 agent,Sweetener Disodium Hydrogen Buffer 100 10 Phosphate Potassium Sorbate,Preservative  5 0.5 NF Flavor Flavor  2 0.2 Purified Water Solvent/ — —suspending solution Total  1000 mg 100

Solvent is removed during manufacture.

In the aspect of Table 7, a drug (e.g., PYY(3-36) can be mixed withexcipients into a solution or suspension, and sprayed to form aparticle. For example, PYY(3-36) and the excipients of Table 7 can becombined with lactose in solution or suspension and spray-dried followedby collection of particles on a filter. See, e.g., Luhn, UsingExcipients In Powder Formulations, Pharmaceutical Technology Europe,Vol. 23, Issue 1 (Jan. 7, 2011); Wu et al., Studies on the spray driedlactose as carrier for dry powder inhalation, Asian Journal ofPharmaceutical Sciences 9 (2014) 336-341.

TABLE 8 Spray-Dried Particles-Example 2 Strength (label claim) Componentand Quantity Quality per unit Standard Function (mg/mL) % PYY₃₋₃₆, humanDrug substance 2.5 ng to 2.5 × 10⁻⁷ to 0.25 2.5 mg Spray-dried LactoseFiller 800 80 Monohydrate Sorbitol Granulating  93 9.3 agent, SweetenerDisodium Hydrogen Buffer 100 10 Phosphate Potassium Sorbate,Preservative  5 0.5 NF Flavor Flavor  2 0.2 Purified Water Solvent/ — —suspending solution Total  1000 mg 100

Solvent is removed during manufacture.

In the aspect of Table 8, the drug and excipients can be wet granulatedwith commercially available spray dried lactose and then dried. See,e.g., Huang et al., Using spray-dried lactose monohydrate in wetgranulation method for a low-dose oral formulation of a paliperidonederivative, Powder Technology 246 (2013) 379-394. In one aspect, thedosage form can be a filled sachet of spray dried particles.

TABLE 9 Spray-Dried Particles-Example 3 Strength (label claim) Componentand Quantity Quality per unit Standard Function (mg/mL) % PYY₃₋₃₆, humanDrug substance 2.5 ng to 2.5 × 10⁻⁷ to 0.25 2.5 mg Anhydrous α Carrier800 80 Lactose Sorbitol Granulating  93 9.3 agent, Sweetener DisodiumHydrogen Buffer 100 10 Phosphate Potassium Sorbate, Preservative  5 0.5NF Flavor Flavor  2 0.2 Purified Water Solvent/ — — suspending solutionTotal  1000 mg 100

Solvent is removed during manufacture.

In the aspect of Table 9, the drug and excipients can be sprayed ontocommercially available lactose or pre-step spray dried lactose, asdescribed. Asian Journal of Pharmaceutical Sciences 9 (2014) 336-341.

In another aspect, the spray-dried particles from, for example, Tables7-9, can be delivered in dry powder inhaler (propellant). In one aspect,the size of the spray-dried particles is between 1 to 10 microns toavoid blocking the orifice of the inhaler device, yet, for example,large enough to be less likely to be inhaled and to be mostly depositedin the mouth. In this aspect, the propellant can be HFA 134a or HFA 227,or a combination of the two. The nozzle design on the inhaler could beadapted to facilitate actuation of a dose to the tongue. In yet anotheraspect, spray-dried particles could be delivered without propellant(e.g., using a unit dose delivery device such as the Aptar pharma UDSdevice).

Further aspects provide microporous polysaccharide microsphere dosageforms.

TABLE 10 Frozen Particles Strength (label claim) Component and QuantityQuality per unit Standard Function (mg/mL) % PYY₃₋₃₆, human Drugsubstance 2.5 ng to 2.5 × 10⁻⁷ to 0.25 2.5 mg Spray-dried Lactose Filler800 80 Monohydrate Sorbitol Granulating  93 9.3 agent, SweetenerDisodium Hydrogen Buffer 100 10 Phosphate Potassium Sorbate,Preservative  5 0.5 NF Flavor Flavor  2 0.2 Purified Water Solvent/ QSto QS to suspending 1000 mL 100 solution Total  1000 mg 100

Further aspects provide exemplary frozen particle dosage forms as shownin Table 10. In one aspect, frozen particle pharmaceutical compositionscomprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In thisaspect, the frozen particle pharmaceutical composition can compriseabout 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this aspect,the pharmaceutical compositions comprise PYY(3-36), a filler, agranulating agent, a buffer, a preservative, and a solvent/suspendingagent. Optional sweeteners and flavorings can be added. In this aspect,the wet granulation method described above with respect to Table 8 canbe used. However, instead of a drying step, the particles can be filledinto sachets of frozen particles and frozen.

Alternatively, a frozen PYY(3-36) solution (Table 11, below) can be usedto fill tubes prior to freezing. Any suitable tube can be used (e.g.,polypropylene tubes used generally for pharmaceuticals, cosmetics, andfood). The tube can be flexible to permit the frozen solution to bedispensed on to the tongue and thawed slowly, for example. In yetanother aspect, the frozen solution can be used in a “blow, fill, seal”dosage form and dispensed in a manner similar to an eye drop ormouthwash dispenser. Markarian, “Blow-fill-seal Technology Advances inAseptic Filling Applications: New advanced aseptic manufacturingtechnologies are available for filling liquid pharmaceuticals, includingbiologics, Equipment and Processing Report, Jun. 18, 2014.

TABLE 11 Frozen Solution Strength (label claim) Component and QuantityQuality per unit Standard Function (mg/mL) % PYY₃₋₃₆, human Drugsubstance 2.5 ng to 2.5 × 10⁻⁷ to 0.25 2.5 mg Sorbitol Granulating 10010 agent, Sweetener Disodium Hydrogen Buffer 100 10 Phosphate PotassiumSorbate, Preservative 5 0.5 NF Flavor Flavor 2 0.2 PolyethyleneStabilizer 100 10 Glycol 8000 Purified Water Solvent/ QS to QS tosuspending 1 mL 100 solution

TABLE 12 Lyophilized Particles Strength (label claim) Component andQuantity Quality per unit Standard Function (mg) % PYY₃₋₃₆, human Drugsubstance 2.5 ng to 5.0 × 10⁻⁶ to 5.0 2.5 mg Trehalose Cryoprotectant/25.5 to 28 51 to 56 Stabilizer Edetate Disodium, Antioxidant 1 2.0Dihydrate, USP Sodium Phosphate, Buffer 3 6.0 Monobasic, Dihydrate, USPPotassium Sorbate, Preservative 2 0.20 NF Hydrochloric Acid pH modifierQS to pH — (HCl), NF, USP 7.0 ± 0.1 Sodium Hydroxide pH modifier QS topH — (NaOH), USP 7.0 ± 0.1 Purified Water Solvent — —

Solvent is removed during manufacture. Diluent can be sterile water ordextrose 5%.

Further aspects provide exemplary lyophilized particle dosage forms asshown in Table 12. In one aspect, lyophilized particle pharmaceuticalcompositions comprising about 2.5 ng 2.5 mg of PYY(3-36) are provided.In this aspect, the lyophilized particle pharmaceutical composition cancomprise about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In thisaspect, the pharmaceutical compositions comprise PYY(3-36), acryoprotectant/stabilizer, an antioxidant, a buffer, preservative(s),optional pH modifiers, and a solvent.

In one aspect, the lyophilized particles are separated from the diluentin a pre-filled oral syringe with mixing chamber. See, e.g.,Vetter-Pharma, Vetter Dual Chamber Systems Website Description. Inanother aspect, the lyophilized particles are separated from the diluentwith a mixing chamber.

TABLE 13 Oral Spray Strength (label claim) Component and QuantityQuality per unit Standard Function (mg) % PYY₃₋₃₆, human Drug substance2.5 ng to 2.5 × 10⁻⁷ to 0.25% 2.5 mg Aspartame Sweetening 30 3 agentEdetate Disodium, Antioxidant 20 2.0 Dihydrate, USP Sodium Phosphate,Buffer 60 6.0 Monobasic, Dihydrate, USP Potassium Sorbate, Preservative2 0.20 NF Peppermint Flavor 10 1 Hydrochloric Acid pH modifier QS to pH— (HCl), NF, USP 7.0 ± 0.1 Sodium Hydroxide pH modifier QS to pH —(NaOH), USP 7.0 ± 0.1 Purified Water Solvent QS to QS to 1 mL 100

Further aspects provide exemplary oral spray dosage forms as shown inTable 13. In one aspect, oral spray pharmaceutical compositionscomprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In thisaspect, the oral spray pharmaceutical composition can comprise about 2.5ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this aspect, thepharmaceutical compositions comprise PYY(3-36), an antioxidant, abuffer, a preservative, a solvent, optional pH modifiers, and optionalflavorings and sweetener agents.

In another aspect, the oral spray can be one device (CCS withactivator), an oral spray with vial adaptor for actuator at the time ofadministration, an oral spray solution to be poured into a device withan actuator, an oral solution in a prefilled oral syringe, an oralsolution in a blow-filled sealed tube, an oral solution in vial or tubewith a measuring device (e.g., dropper, syringe), or a small squeezebottle that dispenses drops (e.g., similar to an optical solution).

TABLE 14 Softgel Capsule Strength (label claim) Component and QuantityQuality per unit Standard Function (mg) % PYY³⁻³⁶, human Drug substance2.5 ng to 2.5 × 10⁻⁷ to 0.25% 2.5 mg Gelatin A Shell 440 44 GlycerinBase 40 4 Sorbitol Sweetening 100 10 Agent Polyethylene Base 30 3 Glycol400 Peppermint Flavor 20 2 Potassium Sorbate, Preservative 2 0.2 NFColor Color 1.5 0.15 Purified Water Solvent QS to QS to 1 mL 100

Further aspects provide exemplary softgel capsule dosage forms as shownin Table 14. In one aspect, softgel capsule pharmaceutical compositionscomprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In thisaspect, the softgel capsule pharmaceutical composition can compriseabout 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this aspect,the pharmaceutical compositions comprise PYY(3-36), a shell (e.g.,gelatin), a base (e.g., glycerin), a second base (polyethylene glycol),a preservative, a solvent, optional flavorings, coloring, and sweeteneragents. In another aspect, the softgel capsule can have a removable nibto open the capsule and pour the contents on to the tongue.

TABLE 15 Mouthwash Strength (label claim) Component and Quantity Qualityper unit Standard Function (mg) % PYY₃₋₃₆, human Drug substance 2.5 ngto 2.5 × 10⁻⁷ to 0.25% 2.5 mg Sucralose Sweetening 30 3 agent EdetateDisodium, Antioxidant 20 2.0 Dihydrate, USP Glycerin Solvent 80 8.0 95%ethanol Solvent, 100 10.0 preservative Peppermint Flavor 200 20 PEG-40Sorbitan Surfactant 400 40.0 Diisosterate Purified Water Solvent QS toQS to 1 mL 100

Further aspects provide exemplary mouthwash dosage forms as shown inTable 15. In one aspect, mouthwash pharmaceutical compositionscomprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In thisaspect, the mouthwash pharmaceutical composition can comprise about 2.5ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this aspect, thepharmaceutical compositions comprise PYY(3-36), an antioxidant, asurfactant, a preservative, and a solvent(s). Optional flavorings andsweeteners may also be added.

TABLE 16 Buccal Tablets-Example 1 Strength (label claim) Component andQuantity Quality per unit Standard Function (mg/mL) % PYY₃₋₃₆, humanDrug substance 2.5 ng to 1.7 × 10⁻⁶ to 1.7 2.5 mg Hydroxypropyl Binder/10 6.7 methylcellulose Mucoadhesive (HPMC) 15 cps Mannitol Sweetener/ 4026.7 Diluent Carbopol 934P Mucoadhesive 10 6.7 Aspartame Sweetener 3 2.0Sodium stearyl, Lubricant 3 2.0 fumarate (SSF) Spray-dried flavor Flavor3 2.0 agent Polyvinyl Dispersant/ 6 4.0 pyrrolidone, K30 mucoadhesiveEthyl cellulose Filler/Binder/ 72.5 to 75 48.3 to 50.0 ViscosityEnhancer/ Mucoadhesive Total 150 100

Further aspects provide exemplary buccal tablet dosage forms as shown inTable 16. In one aspect, buccal tablet pharmaceutical compositionscomprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In thisaspect, the buccal tablet pharmaceutical composition can comprise about2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this aspect, thepharmaceutical compositions comprise PYY(3-36), mucoadhesive(s), adispersant, a preservative, a lubricant, and fillers or binders.Optional flavorings and sweeteners may also be added. See, e.g.,Shirsand et. al., Formulation and optimization of mucoadhesive bilayerbuccal tablets of atenolol using simplex design method, Int J PharmInvestig. 2012 January-March; 2(1): 34-41.

TABLE 17 Buccal Tablets-Example 2 Strength (label claim) Component andQuantity Quality per unit Standard Function (mg) % PYY₃₋₃₆, human Drugsubstance 2.5 ng to 2.1 × 10⁻⁶ to 2.1 2.5 mg Hydroxypropyl Binder/ 30 25methylcellulose Mucoadhesive K4M Carbopol 934P Mucoadhesive 5 4.2Xantham gum Mucoadhesive 30 25 Lactose Diluent/Filler/ 51.3 to 53.8 42.8to 44.8 Binder Magnesium Stearate Lubricant 1.2 1.0 Total 120 100

Further aspects provide exemplary buccal tablet dosage forms as shown inTable 17. In one aspect, buccal tablet pharmaceutical compositionscomprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In thisaspect, the buccal tablet pharmaceutical composition can comprise about2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this aspect, thepharmaceutical compositions comprise PYY(3-36), mucoadhesive(s), alubricant, and diluents, fillers or binders. See, e.g., Chaudhari etal., Formulation and Evaluation of Buccal Tablet of Salbutamol Sulphate,IRJP 2011, 2 (12), 238-242.

TABLE 18 Lyophilized Tablet Strength (label claim) Component andQuantity Quality per unit Standard Function (mg) % PYY₃₋₃₆, human Drugsubstance 2.5 ng to 5.0 × 10⁻⁶ to 5.0 2.5 mg Polyvinyl pyrrolidoneMucoadhesive 2.5 5.0 Carbopol 934P Mucoadhesive 5 10 TrehaloseCryoprotectant/ 25.5 to 28 51 to 56 Stabilizer Edetate Disodium,Antioxidant 1 2.0 Dihydrate, USP Sodium Phosphate, Buffer 3 6.0Monobasic, Dihydrate, USP Polysorbate, 20, NF Surfactant 3 6.0Hydrochloric Acid pH modifier QS to pH — (HCl), NF, USP 7.0 ± 0.1 SodiumHydroxide pH modifier QS to pH — (NaOH), USP 7.0 ± 0.1 Sterile Water forSolvent — — Injection, USP

Solvent Removed During Manufacturing

Further aspects provide exemplary lyophilized tablet dosage forms asshown in Table 18. In one aspect, lyophilized tablet pharmaceuticalcompositions comprising about 2.5 ng-2.5 mg of PYY(3-36) are provided.In this aspect, the lyophilized tablet pharmaceutical composition cancomprise about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In thisaspect, the pharmaceutical compositions comprise PYY(3-36),mucoadhesive(s), a surfactant, a cryoprotectant/stabilizer, anantioxidant, and pH modifiers and solvent.

TABLE 19 Oral Dissolving Tablet (“ODT”) Strength (label claim) Componentand Quantity Quality per unit Standard Function (mg) % PYY₃₋₃₆, humanDrug substance 2.5 ng to 5 × 10⁻⁷ to 1.0 2.5 mg Microcrystaline Binder100 40 cellulose Mannitol Binder 119.75 45.9 Crospovidone Disintegrant25 10 Aspartame Sweetening 5 2 agent FD&C Blue No. 2 Color 0.25 0.1Aluminum Lake Peppermint Flavor 1.25 0.5 Magnesium stearate Lubricant1.25 0.5 Total 250 100

Further aspects provide exemplary ODT tablet dosage forms as shown inTable 19. In one aspect, ODT tablet pharmaceutical compositionscomprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In thisaspect, the ODT tablet pharmaceutical composition can comprise about 2.5ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this aspect, thepharmaceutical compositions comprise PYY(3-36), binder(s), adisintegrant, a lubricant, and optional sweetening agents, flavorings,and lubricants.

In one aspect, the ODT tablet dosage form is a blended powder systemthat is subsequently compressed into tablets using standard rotarypress, and packaged into blister packs or bottles depending on thefriability of the tablets. Finished tablets can have a disintegrationtime of 30 seconds or less on the tongue, for example. Flavoring,coloring, and sweetener levels can be varied as required for end-userexperience.

The compositions described herein can be used to treat a patient in needof treatment as described herein. The terms “treat,” “prevent,” orsimilar terms, as used herein, do not necessarily mean 100% or completetreatment or prevention. Rather, these terms refer to various degrees oftreatment or prevention of a particular disease (e.g., 100%, 90%, 80%,70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1%) as recognized in the artas being beneficial. The terms “treatment” or “prevention” also refer todelaying onset of a disease for a period of time or delaying onsetindefinitely. The term “treatment” or “treating” refers to administeringa drug or treatment to a patient or prescribing a drug to a patientwhere the patient or a third party (e.g., caretaker, family member, orhealth care professional) administers the drug or treatment.

The components of the compositions described herein also encompassderivatives and analogs. In one embodiment, the terms “derivative” or“analogs” include, but are not limited to, ether derivatives, acidderivatives, amide derivatives, ester derivatives and the like. Methodsof preparing these derivatives are known to a person skilled in the art.For example, ether derivatives are prepared by the coupling of thecorresponding alcohols. Amide and ester derivatives are prepared fromthe corresponding carboxylic acid by a reaction with amines andalcohols, respectively.

Any suitable dosage form can be used for delivery of the pharmaceuticalcompositions described herein in addition to dosage forms andformulations described above. In one aspect, the dosage form isespecially suitable for intraoral or oromucosal delivery. In anotheraspect, the dosage form is a lozenge (e.g., planar sheet, solid orsemi-solid candy). In another aspect, the dosage form is a gel, cream,foam, orally disintegrating tablets, or paste. The lozenge can comprisedissolvable material. In another aspect, the dosage form compriseschewing gum. In yet another aspect, the dosage form is a liquidformulation (e.g., emulsion, syrup, elixir, suspension, or a solution,gargles, mouthwashes, gingival solutions, oromucosal solutions andoromucosal suspensions, semi-solid oromucosal preparations (includingfor example gingival gel, gingival paste, oromucosal gel, oromucosalpaste), oromucosal drops, oromucosal sprays and sublingual sprays(including oropharyngeal sprays), lozenges and pastilles, compressedlozenges, sublingual tablets and buccal tablets, oromucosal capsules,mucoadhesive preparations.). In a further aspect, the liquid formulationis a spray or drops for oral administration.

In one aspect, compositions described herein, or a thereof can becompounded or used as a starting material for compounding with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in a unit dosage form as calledfor by accepted pharmaceutical practice. The amount of active substancein compositions or preparations (e.g., active pharmaceuticalingredients) comprising the components of compositions described hereinis such that a suitable dosage in the range indicated is obtained, asdescribed herein.

In another aspect, the components of compositions described herein canbe formulated in a unit dosage form. The term “unit dosage from” refersto physically discrete units suitable as unitary dosages for humansubjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with one or more suitablepharmaceutical excipients.

In one aspect, one or more of the components of compositions describedherein are mixed with or used as starting materials mixed with asuitable pharmaceutically acceptable carrier to form compositions, forexample, as described herein. Upon mixing or addition of thecompound(s), the resulting mixture may be a solution, suspension,emulsion, or the like. Liposomal suspensions may also be used aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. In one aspect, the effective concentration issufficient for lessening or ameliorating at least one symptom of thedisease, disorder, or condition treated and may be empiricallydetermined.

Pharmaceutical carriers or vehicles suitable for administration of thecomponents of compositions described herein include any such carrierssuitable for the particular mode of administration. In addition, theactive materials can also be mixed with other active materials that donot impair the desired action, or with materials that supplement thedesired action, or have another action. The compounds may be formulatedas the sole pharmaceutically active ingredient in the composition or maybe combined with other active ingredients.

In another aspect, if the components of compositions described hereinexhibit insufficient solubility, methods for solubilizing may be used.Such methods are known and include, but are not limited to, usingco-solvents such as dimethylsulfoxide (DMSO), using surfactants such asTWEEN (e.g., polysorbate), and dissolution in aqueous sodiumbicarbonate.

The concentration of the compound is effective for delivery of an amountupon administration that lessens or ameliorates at least one symptom ofthe disorder for which the compound is administered. Typically, thecompositions are packaged for unit dosage administration.

In another aspect, the components of compositions described herein maybe prepared with carriers that protect them against rapid eliminationfrom the body, such as time-release formulations or coatings. Suchcarriers include controlled release formulations, such as, but notlimited to, microencapsulated delivery systems. The active compound canbe included in the pharmaceutically acceptable carrier in an amountsufficient to exert a therapeutically useful effect in the absence ofundesirable side effects on the patient treated. The therapeuticallyeffective concentration may be determined empirically by testing thecompounds in known in vitro and in vivo model systems for the treateddisorder.

In another aspect, the components of compositions described herein canbe enclosed in multiple or single dose containers. The enclosedcompounds and compositions can be provided in kits, for example,including component parts that can be assembled for use. For example,one or more of the compounds (e.g., PYY, PYY(3-36), or analogs) can beused as a starting material for a lyophilized form (e.g., lyophilizedoral dissolving tablet) and a suitable diluent may be provided as aseparated component for combination prior to use. A kit may includecomponents of compositions described herein and a second or thirdtherapeutic agent for co-administration. The components of compositionsdescribed herein and the second or third therapeutic agent may beprovided as separate component parts. A kit may include a plurality ofcontainers, each container holding one or more unit dose of thecomponents of compositions described herein. In one aspect, thecontainers can be adapted for the desired mode of administration,including, but not limited to tablets, gel capsules, sustained-releasecapsules, and the like for oral administration; depot products,pre-filled syringes, ampoules, vials, and the like for parenteraladministration; and patches, medipads, creams, and the like for topicaladministration.

In yet another aspect, the dosage form is lyophilized oral dissolvingtablets. The lyophilized oral dissolving tablets can be modified withthe addition of sugars to produce, for example, a higher Tg Add inlyophilized oral dissolving tablets these can include sugars thatproduce Tg (glass transition temperature) higher than room temperature.See, e.g., Elnggar et al., Maltodextrin: A Novel Excipient Used inSugar-Based Orally Disintegrating Tablets and Phase Transition Process,AAPS Pharm Sci Tech. 2010 June; 11(2): 645-651 (Apr. 20, 2010).

The concentration of the components of compositions described hereinwill depend on dissolution, absorption, metabolism, and excretion ratesof the active compound(s), the dosage schedule, and amount administeredas well as other factors known to those of skill in the art.

In another aspect, the active ingredients may be administered at once,or may be divided into a number of smaller doses to be administered atintervals of time. It is understood that the precise dosage and durationof treatment is a function of the disease being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

If oral administration is desired, the compound can be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an ediblecarrier and may be optionally lyophilized and compressed into tablets orenclosed in gelatin capsules. For the purpose of oral therapeuticadministration, the active compound or compounds can be incorporatedwith excipients and used in the form of tablets, capsules, or troches.Pharmaceutically compatible binding agents and adjuvant materials can beincluded as part of the composition.

The tablets, pills, capsules, troches, and the like can contain any ofthe following ingredients or compounds of a similar nature: a bindersuch as, but not limited to, gum tragacanth, acacia, corn starch, orgelatin; an excipient such as microcrystalline cellulose, starch, orlactose; a disintegrating agent such as, but not limited to, alginicacid and corn starch; a lubricant such as, but not limited to, magnesiumstearate; a glidant, such as, but not limited to, colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; and aflavoring agent such as peppermint, methyl salicylate, or fruitflavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials, whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, chewing gum orthe like. A syrup may contain, in addition to the active compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings, and flavors.

The active materials can also be mixed with other active materials thatdo not impair the desired action, or with materials that supplement thedesired action. The components of compositions described herein can beused, for example, in combination with an anti-obesity, anti-diabetes,or similar drug (e.g., lorcaserin, orlistat, phentermine/topiramate,sibutramine, rimonabant, metformin, exenatide, liraglutide, pamlintide,naltrexone, and tesofensine).

In one aspect, solutions or suspensions used for parenteral, pumpdelivery, intradermal, subcutaneous, or topical application can includeany of the following components: a sterile diluent such as water forinjection, saline solution, fixed oil, a naturally occurring vegetableoil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and thelike, or a synthetic fatty vehicle such as ethyl oleate, and the like,polyethylene glycol, glycerin, propylene glycol, or other syntheticsolvent; antimicrobial agents such as benzyl alcohol and methylparabens; antioxidants such as ascorbic acid and sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid (EDTA) or itsdisodium salt; buffers such as acetates, citrates, and phosphates; andagents for the adjustment of tonicity such as sodium chloride anddextrose. Parenteral preparations can be enclosed in ampoules,disposable syringes, or multiple dose vials made of glass, plastic, orother suitable material. Buffers, preservatives, antioxidants, and thelike can be incorporated as required.

Where administered intravenously, suitable carriers include, but are notlimited to, physiological saline, phosphate buffered saline (PBS), andsolutions containing thickening and solubilizing agents such as glucose,polyethylene glycol, polypropylene glycol, and mixtures thereof.Liposomal suspensions including tissue-targeted liposomes may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known in the art.

In another aspect, the components of compositions described herein maybe prepared with carriers that protect the compound against rapidelimination from the body, such as time-release formulations orcoatings. Such carriers include controlled release formulations, suchas, but not limited to, implants and microencapsulated delivery systems,and biodegradable, biocompatible polymers such as collagen, ethylenevinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters,polylactic acid, hydroxyl propyl methyl cellulose (HPMC), othercellulose derivatives, and the like. Methods for preparation of suchformulations are known to those skilled in the art.

In yet another aspect, compounds employed in the methods of thedisclosure may be administered enterally or parenterally. Whenadministered orally, compounds employed in the methods of the disclosurecan be administered in usual dosage forms for oral administration as iswell known to those skilled in the art. These dosage forms include theusual solid unit dosage forms of tablets and capsules as well as liquiddosage forms such as solutions, suspensions, and elixirs. When the soliddosage forms are used, they can be of the sustained release type so thatthe compounds employed in the methods described herein need to beadministered only once or twice daily.

The oral dosage forms can be administered to the patient 1, 2, 3, or 4times daily, or as needed. The components of compositions describedherein can be administered either three or fewer times, or even once ortwice daily. Whatever oral dosage form is used, it can be designed so asto protect the compounds employed in the methods described herein fromthe acidic environment of the stomach. Enteric coated tablets andcapsules filled with small spheres, each coated to protect from theacidic stomach, are also well known to those skilled in the art and canbe used with aspects described herein.

The terms “therapeutically effective amount” and “therapeuticallyeffective period of time” are used to denote treatments at dosages andfor periods of time effective to treat, ameliorate, or reduce conditionsor symptoms described herein.

One of skill in the art will appreciate that such therapeutic effectresulting in a lower effective concentration of the components ofcompositions described herein may vary considerably depending on thetissue, organ, or the particular animal or patient to be treated. It isalso understood that while a patient may be started at one dose, thatdose may be varied overtime as the patient's condition changes.

It should be apparent to one skilled in the art that the exact dosageand frequency of administration will depend on the particular compoundsemployed in the methods of the disclosure administered, the particularcondition being treated, the severity of the condition being treated,the age, weight, general physical condition of the particular patient,and other medication the individual may be taking as is well known toadministering physicians who are skilled in this art.

EXAMPLES Example 1—PYY(3-36) Dose Escalation Study

Day 1 (Check into Study Unit and Placebo Administration)

Subjects who complete all screening procedures and meet all inclusionand exclusion criteria described within the protocol and found to beeligible for study enrollment checked into the Study Unit (i.e., thestudy facility). The morning of the study, participants fasted prior toarriving at the SU. Participants fasted for at least 12 hours prior toDay 1 of the study. Participants were permitted to only drink waterprior to arrival to SU and were able to brush their teeth. The followingassessments and measurements were taken:

(1) Inspection of the lingual mucosa.

(2) Updating medical and medication history prior to placeboapplication.

(3) Assessing health status. If participant has either rhinitis orgastrointestinal distress, the participant will be discontinued for thatday.

(4) Measuring body weight and BMI.

(5) Measuring vital signs (BP, HR, and body temperature). BP and HR weremeasured twice in the sitting position and twice in the standingposition. If BP was high at baseline sitting (>160 systolic), BP wasre-checked after participant was sitting for 5-10 min. Body temperaturewas measured once.

(6) Performing urine drug screen, urine cotinine test, alcohol breathtest, and urine pregnancy test.

(7) Subjects provided a 325-400 calorie breakfast and calorie intake wasrecorded.

(8) Water was provided “ad-libitum” and volume recorded.

(9) Four (4) hours post breakfast, the VAS for Appetite and Satiety wasperformed.

(10) Inserting a cannula to obtain blood samples, obtaining a 5 ml bloodsample, and screening for anti-GT-001 antibodies.

(11) Obtaining a fasting PK blood sample #1 (5 ml) 15 minutes prior toplacebo.

(12) Performing a water mouthwash prior to dosing with GT-001. Themouthwash can be a rinse with 20 ml of water.

(13) Giving one milliliter (1 ml) of placebo (formulation withoutGT-001) to the participant to the tongue via pipette 5 minutes beforelunch.

(14) The solution remained on the tongue for 1 minute followed by askingparticipants to swish and then swallow.

(15) Completing a VAS for like-lines (VAS completed by subjects).

(16) Collecting PK blood samples after each of seven doses at ±1 minuteat 5, 10, 15, 30, and ±5 minutes at 60, 120, and 240 minutes post dose.

(17) Isolating subjects from other subjects during lunch.

(18) Provided a “ad-libitum” lunch (composed of a casserole, nutrientdrink and two (2) cookies) and recording calorie intake.

(19) Having subjects complete VAS questionnaire for sweetness, sourness,bitterness, saltiness, umami, and fat taste 20 minutes after completingthe meals.

(20) Recording VAS for appetite and satiety every 30 minutes for 2 hoursafter completing the meal.

(21) Discharging subjects. Subjects ate “at-libitum” until the 12-hourfasting period preceding the next study visit.

(22) During the SU visit, subjects were restricted from ingesting gum,candy, tobacco, carbonated drinks, and from performing exercise. Duringthe meal, subjects were not exposed to food cues (visual, odor, orhearing) and they should eat in isolation.

Days 2, 4, 6, 8, 10, 12 and 14 treatment days are the same as day 1.

Days 3, 5, 7, 9, 11, and 13: Washout days

Participants rest at home.

Study End (Day 15 and Early Termination Visit

If an enrolled subject completed day 1-14, or discontinued from thestudy prior to the planned SU discharge, the following was completed:

(1) Recording reason for discontinuation from the study.

(2) Updating medical and medication history.

(3) Completing adverse event assessment.

(4) Measuring vital signs (BP, HR, and body temperature). BP and HR weremeasured twice in the sitting position and twice in the standingposition. If BP is high at baseline sitting (>160 systolic), BP wasre-checked after participant is sitting for 5-10 minutes. Bodytemperature was measured once.

(5) Measuring body weight and BMI.

(6) Performing physical examination, including inspection of the lingualmucosa.

(7) Conducting clinical laboratory tests (serum chemistry, hematology,and urinalysis).

(8) Measuring GT-001 serum level with anti-GT-001 antibodies.

(9) Giving serum pregnancy test.

(10) Performing urine drug screen, urine cotinine test, and alcoholbreath test.

(11) Diet: Meals details

(a) Breakfast: Participants provided with macronutrient balancedbreakfast (approximately 325-400 calories). Participants selected theirtype of breakfast between eggs, cereal, toast, etc. Juices, milk andcoffee were permitted within the allotted calories. No artificialsweeteners were permitted.

(b) Lunch: Participants provided with all you can eat casserole,juice/milk, and two (2) cookies. Total food intake and VAS appetite andsatiety was recorded. No artificial sweeteners were permitted.

(c) In between meals: Participants can only have water in between meals.Participants were restricted from gum, candy, tobacco, and carbonateddrinks.

Example 2—VAS Assessment

The following exemplary VAS Assessment was given to subjects to assesstheir feeling of fullness before and after receiving PYY(3-36) orplacebo and before or after eating at various doses described herein.Participants indicated their response on a scale of 1-10 with 1indicating the strongest response on the left and 10 indicating thestrongest response on the right. For example, if a participant indicateda response of 1 for question a, they were not hungry at all. A responseof 10 for question a indicated they have never been hungrier. A responseof 5 indicates they felt in between “I am not hungry at all” and “I havenever been more hungry.” The numerical responses on a scale of 1-10 weretabulated and used to generate the graphs of FIGS. 1 and 2.

a I am not hungry at all How hungry do you feel? I have never been morehungry b I am comptetely empty How satisfied do you feel? I cannot eatanother bite c Not at all full How full do you feel? Totally full dNothing at all How much do you think you can eat? A lot

REFERENCES

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1. A pharmaceutical composition comprising an agent selected from the group consisting of leptin, amylin, calcitonin, gastric inhibitory peptide (GIP), fibroblast growth factor (FGF21), and insulin, wherein the composition provides satiation to a subject without substantially changing the concentration of the agent in the plasma of the subject, and wherein the composition is formulated as an oral dissolving tablet.
 2. The pharmaceutical composition of claim 1, further comprising from about 2.5 ng to about 2.5 mg Peptide YY (PYY). 3-9. (canceled)
 10. A pharmaceutical composition comprising an agent selected from oxyntomodulin (OXM) and cholecystokinin (CCK) in a dose of from about 2.5 ng to about 2.5 mg, wherein the composition provides satiation to a subject without substantially changing the concentration of the agent in the plasma of the subject, and wherein the composition is formulated as an oral dissolving tablet.
 11. The pharmaceutical composition of claim 10, further comprising from about 2.5 ng to about 2.5 mg PYY. 12-14. (canceled)
 15. A pharmaceutical composition comprising an agent selected from the group consisting of acetyl-CoA carboxylase inhibitor, a diacylglycerol O-acyltransferase 1 inhibitor, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase-10 inhibitor, an AMP-activated protein kinase activator, a sulfonylurea, a meglitinide, an α-amylase inhibitor, an α-glucoside hydrolase inhibitor, an α-glucosidase inhibitor, a peroxisome proliferator-activated receptor (PPAR) gamma agonist, a PPAR α/γ agonist, a biguanide, a protein tyrosine phosphatase-1B inhibitor, sirtuin-1 activator, a dipeptidyl peptidase IV inhibitor, an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase inhibitor, glucokinase activators, an insulin mimetic, a glycogen phosphorylase inhibitor, a vasoactive intestinal peptide receptor 2 receptor agonist, a sodium glucose co-transporter 2 inhibitor, a glucagon receptor modulator, a G protein-coupled receptor 19 modulator, a free fatty acid receptor 1 agonist, a free fatty acid receptor 4 modulators, a high affinity nicotinic acid receptor activator, a sodium-D-glucose cotransporter inhibitor, an inhibitor or modulator of a carnitine palmitoyl transferase enzyme, a fructose 1,6-diphosphatase inhibitor, an aldose reductase inhibitor, a mineralocorticoid receptor inhibitor, a target of rapamycin kinase multiprotein complex inhibitor, a C—C chemokine receptor type 2 and/or a C—C chemokine receptor type 5 inhibitor, a protein kinase C inhibitor, a fatty acid synthetase inhibitor, a serine palmitoyl transferase inhibitor, a G protein-coupled receptor 81 modulator, a G protein-coupled receptor 39 modulator, a G protein-coupled receptor 43 modulator, a G protein-coupled receptor 41 modulator, a G protein-coupled receptor 105 modulator, voltage-gated potassium channel, retinal binding protein 4, glucocorticoid receptor, a somatostatin receptor, an inhibitor or modulator of pyruvate dehydrogenase kinase isoform 2 or pyruvate dehydrogenase kinase isoform 4, an inhibitor of mitogen-activated protein kinase kinase kinase kinase 4, an interleukin 1 modulator, a 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, a squalene synthetase inhibitor, a fibrate, a bile acid sequestrant, an acyl-CoA cholesterol acyltransferase, a microsomal triglyceride transfer protein, a lipooxygenase inhibitor, a cholesterol absorption inhibitor, a proprotein convertase subtilisin/kexin type 9 modulator, a cholesteryl ester transfer protein inhibitor, a modulator of retinoid x receptor α, enterostatin or an enterostatin analog, a ghrelin modulator, a pancreatic polypeptide, neuropeptide Y, human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, ghrelin, and glucagon, wherein the composition provides satiation to a subject without substantially changing the concentration of the agent in the plasma of the subject, and wherein the composition is formulated as an oral dissolving tablet.
 16. The pharmaceutical composition of claim 15, further comprising from about 2.5 ng to about 2.5 mg PYY.
 17. (canceled)
 18. A method of treating a metabolic disorder in a subject comprising administering the pharmaceutical composition of claim 1 to the tongue of the subject, wherein the composition provides satiation to a subject without substantially changing the concentration of the agent in the plasma of the subject.
 19. The method of claim 18, wherein the pharmaceutical composition further comprises from about 2.5 ng to about 2.5 mg PYY. 20-22. (canceled)
 23. A method of treating a metabolic disorder in a subject comprising administering the pharmaceutical composition of claim 10 to the tongue of the subject in a dose of from about 2.5 ng to about 2.5 mg, wherein the composition provides satiation to a subject without substantially changing the concentration of the agent in the plasma of the subject.
 24. The method of claim 23, wherein the pharmaceutical composition further comprises from about 2.5 ng to about 2.5 mg PYY. 25-27. (canceled)
 28. A method of treating a metabolic disorder in a subject comprising administering the pharmaceutical composition of claim 15 to the tongue of the subject wherein the composition provides satiation to a subject without substantially changing the concentration of the agent in the plasma of the subject.
 29. The method of claim 28, wherein the pharmaceutical composition further comprises from about 2.5 ng to about 2.5 mg PYY. 30-32. (canceled) 